Calcium is essential for a number of key functions in the body, both as ionized calcium and a calcium complex (Campell A K. Clin Sci 1987; 72:1-10). Cell behaviour and growth are regulated by calcium. In association with troponin, calcium controls muscle contraction and relaxation (Ebashi S. Proc R Soc Lond 1980; 207:259-86).
Calcium selected channels are a universal feature of the cell membrane and the electrical activity of nerve tissue and the discharge of neurosecretory granules are a function of the balance between intracellular and extra cellular calcium levels (Burgoyne R D. Biochim Biophys Acta 1984; 779:201-16). The secretion of hormones and the activity of key enzymes and proteins are dependent on calcium. Finally calcium as a calcium phosphate complex confers rigidity and strength on the skeleton (Boskey A L. Springer, 1988:171-26). Because bone contains over 99% of the total body calcium, skeletal calcium also serves as the major long-term calcium reservoir.
Calcium salts such as, e.g., calcium carbonate is used as a source of calcium especially for patients suffering from or at risk of osteoporosis. Moreover, calcium carbonate is used as an acid-neutralizing agent in antacid tablets.
Furthermore, calcium may have anticancer actions within the colon. Several preliminary studies have shown high calcium diets or intake of calcium supplementation is associated with reduced colon rectal cancer. There is increasing evidence that calcium in combination with acetylsalicylic acid (ASA) and other non-steroidal anti-inflammatory drugs (NSAIDS) reduce the risk the risk of colorectal cancer.
Recent research studies suggest that calcium might relieve premenstrual syndrome (PMS). Some researchers believe that disruptions in calcium regulation are an underlying factor in the development of PMS symptoms. In one study, half the women of a 466 person group of pre-menopausal women from across the U.S. were tracked for three menstrual cycles and were given 1200 mg of calcium supplements daily throughout the cycle. The final results showed that 48% of the women who took placebo had PMS related symptoms. Only 30% of those receiving calcium tablet did.
Calcium salts like e.g. calcium carbonate is used in tablets and due to the high dose of calcium required, such tablets are often in the form of chewable tablets. It is a challenge to formulate chewable tablets containing a calcium salt, which tablets have a pleasant taste and an acceptable mouthfeel without the characteristic dominating taste or feeling of chalk.
Furthermore, i) the high dose of calcium carbonate (normally 300-600 mg of elemental calcium twice daily, corresponding to 750-1500 mg of calcium carbonate twice daily), ii) the inherent poor properties of regular shaped calcium carbonate with respect to tabletting properties like compressibility, which accordingly calls for the need of adding one or more pharmaceutically acceptable excipients in order to obtain a suitable compressibility, and iii) the extremely bad taste or mouthfeel of a calcium salt itself especially with respect to chalkiness make it very difficult to prepare a tablet that has a suitable small size, which is conveniently small for a patient. Sufficient taste masking is another major challenge when formulating chewable tablets.
The present inventors have found an easy way for producing e.g. chewable tablets containing a physiologically tolerable calcium-containing compound by using a granulate comprising agglomerates of the calcium-containing compound. The granulate is obtained without use of any solvent (e.g. water), but involves the technique of roller compaction of the calcium-containing compound to form agglomerates having suitable properties for further processing into a solid dosage form such as, e.g., tablets.
EP 0 054 333 (Stauffer Chemical Company) describes a process of compacting fine particles of calcium phosphate by means of roller compacting to obtain a powder. The powder obtained has a larger bulk density than the starting material, which makes it suitable for use as an excipient in producing pharmaceutical tablets. In contrast to EP 0 054 333 the present invention does not employ roller compaction with the aim of increasing the bulk density of a pharmaceutically acceptable excipient, but as a novel method for agglomeration, i.e. for building up agglomerates of particles in order to increase the mean particle size to a size that is suitable for further processing of the material into e.g. tablets such as, e.g., chewable tablets that have an acceptable taste and/or mouthfeel.
Previously it has been described that the quality of the calcium-containing compound as well as the method for preparation of a pharmaceutical composition containing the calcium-containing compound are of great importance in order to obtain acceptable taste and mouthfeel of a chewable tablet (WO 00/28973). In contrast to WO 00/28973 the method according to the invention does not employ a step of binding the particles together by a wet granulation process, which means that the method according to the invention advantageously can be employed when it is desired to incorporate substances that are sensitive towards humidity. An example of such a substance is vitamin D that often is included together with a calcium salt in a pharmaceutically dosage form. The present invention provides a simple and cost-effective alternative method to obtain such a dosage form without the need of a step e.g. involving wet granulation.